2013年3月13日訊 /生物谷BIOON/ --來自伊利諾伊大學(xué)的Madhu Gupta教授帶領(lǐng)他的團隊在《生物化學(xué)雜志》（Journal of biological chemistry）上在線發(fā)表了題為"A cardiac enriched microRNA, miR-378 blocks cardiac hypertrophy by targeting Ras-signaling"的文章,。文章中指出,，他們發(fā)現(xiàn)在心肌細胞中富集表達的microRNA-378通過靶向Ras信號通路,，參與抑制心肌肥厚的發(fā)生。
心肌肥厚指心肌細胞增大而無細胞分裂,，是心肌細胞對高血壓,、瓣膜病、急性心肌梗塞及先天性心臟病等疾病的一種基本應(yīng)答,，長期應(yīng)激所致的持續(xù)性心肌肥厚最終可導(dǎo)致擴張性心肌病,、心衰和猝死。已有研究表明,，Ras信號通路在心肌肥厚過程中發(fā)揮了重要作用,，Ras通路通過激活下游IGF-PI3K-AKT-mTOR和Raf1-MEK1-ERK1/2兩條通路，引起心肌肥厚的發(fā)生,。
MicroRNA（miRNA）是一類內(nèi)源產(chǎn)生的,，長約22nt的單鏈非編碼小RNA，參與轉(zhuǎn)錄后基因表達調(diào)控,。眾多miRNA被證明在心臟發(fā)育和心臟疾病發(fā)生過程中發(fā)揮著重要功能,，僅在心肌細胞中特異性表達的miR-378就是其中之一。本文就miR-378在刺激劑導(dǎo)致的心肌肥厚過程中發(fā)揮的作用進行了系統(tǒng)性的研究,。
在此項研究中,，研究者們探索了miR-378的表達和心肌肥厚的相互關(guān)系，他們發(fā)現(xiàn),，在刺激劑導(dǎo)致的心肌肥厚過程中miR-378的表達被抑制,，這一結(jié)果在細胞水平和動物水平都得到了驗證，同時,，過表達miR-378可以有效的阻滯此類心肌肥厚的發(fā)生,。這一結(jié)果證實，miR-378確實參與了刺激劑導(dǎo)致的心肌肥厚的發(fā)生過程,，起著負調(diào)節(jié)的作用,。
在進一步的研究中，研究人員對miR-378所參與的信號通路進行了探索,。他們對刺激劑引起的心肌肥厚過程中幾條重要的信號通路進行研究,，發(fā)現(xiàn)miRNA-378通過對Ras通路進行負調(diào)節(jié)從而抑制了MAPK/ERK和PI3K/AKT兩條通路的激活。通過使用生物信息學(xué)預(yù)測,，研究者們對這條通路上可能存在的miR-378靶點進行了分析和實驗驗證,，結(jié)果表明，miR-378靶向Ras通路上游的Grb-2,，通過抑制該蛋白的表達從而對Ras通路進行負調(diào)控,。
此項研究指出了miR-378在心肌肥厚過程中起到的重要作用，為心肌肥厚引起的心臟疾病的治療研究提供的新的思路,。（生物谷Bioon.com）
doi:10.1074/jbc.M112.442384
A cardiac enriched microRNA, miR-378 blocks cardiac hypertrophy by targeting Ras-signaling
Raghu S. Nagalingam1, Nagalingam R. Sundaresan2, Mahesh P. Gupta2,Dave Geenen1, R. John Solaro1 and Madhu Gupta1,*
Understanding the regulation of cardiomyocyte growth is crucial for the management of adverse ventricular remodeling and heart failure. MicroRNA-378 (miR-378) is a newly described member of the cardiac enriched miRNAs which is expressed only in cardiac myocytes and not in cardiac fibroblasts. We have previously shown that miR-378 regulates cardiac growth during post-natal period by direct targeting of IGF1R (J Biol Chem 287, 12913-12926, 2012). Here, we report that miR-378 is an endogenous negative regulator of cardiac hypertrophy, and its levels are down regulated during hypertrophic growth of the heart and during heart failure. In primary cultures of cardiomyocytes, over expression of miR-378 blocked PE-stimulated Ras-activity and it also prevented activation of two major growth-promoting signaling pathways, PI3K-AKT and Raf1-MEK1-ERK1/2, acting downstream of Ras-signaling. Over expression of miR-378 suppressed PE-induced phosphorylation of S6 ribosomal kinase, pERK1/2, pAKT, pGSK3β and nuclear accumulation of NFAT. There was also suppression of fetal gene program that was induced by PE. Experiments carried out to delineate the mechanism behind the suppression of Ras, led us to identify Grb2, an upstream component of Ras-signaling, as a bone-fide direct target of miR-378-mediated regulation. Deficiency of miR-378 alone was sufficient to induce fetal gene expression, which was prevented by knocking down of Grb2 expression and by blocking of Ras-activation, thus suggesting that miR-378 interferes with Ras-activation by targeting Grb2. Our study demonstrates that miR-378 is an endogenous negative regulator of Ras-signaling and cardiac hypertrophy and its deficiency contributes to the development of cardiac hypertrophy.
